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Line Chemotherapy for Advanced Non-Small Cell Lung Cancer in China

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Line Chemotherapy for Advanced Non-Small Cell Lung Cancer in China

    Line Chemotherapy for Advanced

    Non-Small Cell Lung Cancer in China www.springerlink.comChinJCancerRes22(1):12010

    APhaseIITrialofGefitinibasMaintenanceTherapyafterFirst-Line ChemotherapyforAdvancedNon-SmallCellLungCancerinChina

    LuYang,Zhi.jieWang,Tong.tongAn,HuaBai,JunZhao,

    Ping.pingLi,Mei.naWu,HongSun,LiLiang,JieWang

    Jian.chunDuan,

    TheKeyLaboratoryofCarcinogenesisandTranslationalResearch(MinistryofEducation);Department

    ofThoracicMedicalOncology,DepartmentofTraditionalChineseMedicineCombinedWestMedical

    Oncology,PekingUniversitySchoolofOncology,BeUingCancerHospital&Institute,Beijing100142,

    China,DepartmentofOncology,theThirdHospitalofPekingUniversity,Beijing100083,China

    CLCnumber:R734.2Documentcode:AArticleID:1000-96O4(2O1O)O1-0001-09 DoI:1O.1OO7/sll67O.010.0001.3

    ?ChineseAntiCancerAssociationandSpringerVerlagBerlinHeidelberg2010

    ABSTRACT

    Objective:Toinvestigatetheefficacyandsafetyofgefitinibasmaintenancetherapyforadvancednonsmall

    celllungcancer(NSCLC)patientswhoobtaineddiseasecontrolfDC)afterfirst

    linechemotherapyinChinese

    population.

    Methods:ChinesepatientswithadvancedNSCLCtreatedwithstandardchemotherapyandobtainedDCwere

    assignedtoreceivegefitinibasmaintenancetreatment.Theprimaryendpointwasoverallsurvivaltime(0S),the

    secondendpointwasdiseasecontrolrate(DCR)andprogression.freesurvivaltime(PFS).DCRincludedcomplete

    response(CR)pluspartialresponse(PR)andplusstabledisease(SD).Theimpactofepidermalgrowthfactor

    receptorfEGFR)mutationstatusonthetreatmentasexploratorypointwasalsoevaluatedbydenaturing

    high.performanceliquidchromatography(DHPLC).

    Results:Among75enrolledpatients,theoverallresponseratewas37%andtheDCRfCR+PR+SD)was66%.

    ThemedianPFSandOSwere17.13monthsand26.13monthsrespectively.with1.and2.yearsurvivalrates89.3%

    and34.7%.PatientsharboringsomaticEGFRmutationsobtainedaprolongedmedianPFSandOScomparedwith

    EGFRwidetype(25.1vs.13.0months,P=O.0l9and33.37vs.25.57months,P=0.014,respectively).InCOX

    regressionmodel,onlyEGFRmutationstatuswastheindependentlyfactorinfluencingbothPFSandOS(P=0.029

    and0.017,respectjve1y),however,rashstatuswasthepredictorintermsofPFS(p=0.027). Conclusion:GefitinibproducedencouragingsurvivalwhendeliveredasmaintenancetherapyinChinese

    patientsobtainingDCafterfirst-linechemotherapy,especiallyforpatientscarryingsomaticEGFRmutations.

    EGFRmutationisanindependent1ypredictivefactorofsurviva1.

    Keywords:Gefitinib;Maintenancetherapy;Nonsmallcelllungcancer

    INTRoDUCTIoN

    Nonsmallcelllungcancer(NSCLC)accounts

    Received2009-09-l6:Accepted2009-l2-30

    ThisworkwassupportedbythegrantsfromtheNational''863''

    HighTechnologyResearchandDevelopmentProgramofChina (No.2006AA02A401)andtheCapitalDevelopmentFoundation ofBeijingrNo.3077221,47

    'Contributedequallytothisstudy.

    ?corresp0ndinauhor.

    

    Email:wangjiecc@yahoo.com

    for80%to85%burdenoflungcancerwhichisthe leadingcauseofcancer.relateddeathinthe world?J.Thecurrenttreatmentstrategyfor advancedNSCLCincludesfirstlinechemotherapy

    usingaplatinum.basedregimen,withtheaddition ofthetargetedagentbevacizumabforcertain patientsL.Anumberofchemotherapeuticagents. includinggemcitabine,docetaxel,andpaclitaxel, areactiveinfirst.1inetreatmentaspartofa platinum.basedcombination41.Despiteslight

    improvementinthesurvivalrate,theeffectsreach 2ChinJCancerRes21l3):19,2009www.springerlink,corn aplateauimpedingfurtherefficacy.Recently, maintenancetherapyasanovelstrategyhasdrawn extensiveattention.However,whetherthiskindof therapycouldimprovesurvivalremained cOntrOversia1.

    TheOreticaUv,patientswhohaveobtained objectiveresponseordiseasestabilization followinginitialchemotherapywouldhavea reducedtumorburdenorreducedtumorgrowth. Thesetumorsmaybenefitfromearlyuseofnon

cross.resistanceagents61.Astimulatingoutcome

    currentlyreportedbyCiuleanueta1.Lseemedto verifytheaforementionedtheoryandshowedthat pemetrexedasmaintenancetherapyprovided survivalimprovementinselectivepatientswith adenocarcinomawhichalsosuggeststhat appropriateagentsforappropriatepatientsmaybe akeyfactorforprogressiontowardscontrolling cancer.Withbetterunderstandingandexploitation ofcancerbiology.epiderma1growthfactor receptor.tyrosinekinaseinhibitorsfEGFRTKI1

    havebeendevelopedasvalidatedtargeted anticanceragentsandapprovedforclinicaluse. Gefitinibanderlotinibaretherepresentiveagents bothofwhichhavedemonstratedidenticalefficacy andlowertoxicitycomparedwithcellulartoxicity agentsandthereforehavebeenusedinclinical extensively【一….Basedonthesetheoreticaland

    clinicalevidences.weassumedthatEGFRTKI

    Allpatientsprovidedwritteninformedconsent. Thestudywasconductedinlinewiththe

    DeclarationofHelsinki,theInternational ConferenceonHarmonization/GpodClinical Practice,andapplicableregulatoryrequirements. Patients

    Patientswereeligibleiftheymetthefollowing criteria:morethan18years;histOlOgicallVor cytologicallyconfirmed,unresectable,stageIII B/IVNSCLC;EasternCooperativeOncology Groupperformance(ECOG)status0-2:atleast2

coursesofpriorstandardfirstlinechemotherapy,

    nolongerthan2mbetweenthelastchemotherapy andtheinitialdoseofgefitinib:fullrecoveryfrom toxicitiesduetopriortherapy;adequate hematological,renal,andhepaticfunction:life expectancylongerthan3m:negativepregnancy testforwomenofchildbearingpotentia1.

    Notableexclusioncriteriawere:evidenceof unstablesystemicdisease;priortreatmentwith anti.EGFRagents:previousmalignancies(1ast5 years,otherthansuccessfultreatmentforcervical carcinoma/skincancer):untreatedbrainmetastases orspinalcordcompression;significant ophthalmologicabnormalities(e.g.,severedryeye syndrome,keratoconjunctivitissicca,Sj6gren syndrome,severeexposurekeratitis).

    couldprovidefurthersurvivalbenefitasa maintenancetreatment.TreatmentPlan

    TheaimofthepresentphaseIItrialwe

    designedwastoassesstheefficacyandsafety profilesofgefitinibasmaintenancetherapyfor patientshavingachievedatleasttumor

    stabilizationafterfirst.1inechemotherapy. Additionally,anexploratoryendpointwasto investigatethecorrelationofsurvivalwithEGFR mutatjonstatus.

    PATIENTSANDMETHoDS

    TrialDesign

    Thetrialisanopen.1abelsinglearmstudyof

    gefitinibdeliveredimmediatelyasmaintenance

    therapyinpatientswithadvanced(inoperablestage IIIBorIV1NSCLCwhoobtainedDCafter

    standardfirst.1inechemotherapy.Patientsenrolled inthetrialreceivedgefitinibatleastonemonth, andthetumortissuesampleswereobtained immediatelybeforestartinggefitinibthroughcore needlebiopsy,bronchoscOpicbiopsyorsurgical resection.

    A11patientsreceivedstandardfirst.1ine chemotherapyincludingplatinumbaseddoublet

    regimens(cis,carbop1atinplusgemcitabine,taxane ornovelbinerespective1y).Totalcyclesnumber wasnomorethan6cycles.Patientswerethen switchedtoreceivegefitinib250mgorallyperday iftheycompleted4-6cyclesofchemotherapyor underwentunacceDtablechemotherapyassociated toxicity.Gefitinibtreatmentcontinueduntil intolerabletoxicity,diseaseprogressionordeath, orwithdrawa1.Doseinterruption/reductiOnwas permittedfortreatment.relatedadverseevents. ClinicalAssessments

    TumorresponsewasassessedusingResponse EvaluationCriteriainSolidTumors,atleastevery 6wduringtheperiodofchemotherapyandnomore than3minthegefitinibtreatmentphase.

    Responseswereconfirmedafter4w.Overall survival(OS)andprogressionfreesurvival(PFS)

    werecalculatedfromthedateofstartingfirst.1ine chemotherapytothedateofdeath/dateofdisease

www.springerlink,cornChinJCancerRes22(1):19.2010

    progressionordeath,respectively.Clinical assessmentswereatbaselineandthenevery4w. Theassessmentsofadverseeventswere

    recordedaccordingtoNationalCancerInstitute CommonToxicityCriteria3.0(NCI-CTC3.0). EGFRMutationDetection

    Paraffin.embeddedtumormaterialwascutinto 4gmthicksectionsandplacedontoglassslides, stainedwithH&E.andthepresenceoftumorwas verifiedbyapathologist.Detailedmethodswere describedinourpriorpaper".

    StatisticalAnalysis

    TheprimaryendpointofthisstudywasOS. Previousprospectivetrialsshowed1.yearsurvival ratewas20%-46%(mean:33%1inpatients

    receivingchemotherapywiththirdgeneration agents(Gemicitabine,Paclitaxel,Docetaxe1)in combinationwithplatinum.Basedonthe

    historicalcontrolbenchmark,arelative improvementof3O%inl_yearsurvivalrateforthe patientsreceivinggefitinibasmaintenancetherapy aftergainedDCunderfront.1inechemotherapywas consideredsnfficientevidencetomovearegimen intoaphaseIllstudy.So.57assessablepatients wereplanedtobeenrolledinourtria1.Considering thedifficultofobtainingsufficienttissuesamples andcensoredcases,aplanedassignmentofmore than70patientstoourtreatmentregimenwould providea90%statisticalpowertofindan

    improvementof30%in1.yearsurvivalrate.with P=0.05(two.sided)assignificanceleve1. Survivalanalysiswasconductedonall75 patients,andtherewere62forwhomEGFR mutationanalysiscouldbesuccessfullyperformed. Thedifferenceinmutationrateamonggroups categorizedbysmokingexposurewasexamined with?C2test.

    ThePFSandOScurveswereplottedusingthe KaplanMeiermethodandsurvivalcurve

    comparisonswereconductedwiththelogranktest.

    Multivariateanalysisoftheimpactofthefactors. includingEGFRmutationstatusandclinical characteristicswereconductedusingtheCox regressionmode1.A11analysiswasdeterminedto bestatisticallysignificantwheretheP.valuewas< 0.05.Forstatisticalanalyses.weusedSPSS softwareforPC(version13.0forwindows). RESUIrS

    PatientCharacteristics

    Theintenttotreatpopulation(n=75)

    comprisedallregisteredpatientsfromNovember1, 2005toApril1.2009withhisto1ogicallyor cytologicallyconfirmedadvancedNSCLCfrom twoC:hinesecancercenterincludingBeijing CancerHospitalandtheThirdHospitalofPeking Universitywhoreceived250mg/daygefitinib orallyasmaintenancetreatmentafterdisease controlledfirst.1inechemotherapy.Table1 summarizesthedemographicandbaseline

    clinical/tumorcharacteristics.Themajorityofthe patientshadperformancestatusfPS)scoreof0orl andhighpercentageofpatientshadthe

    characteristicoffemale.neversmokingor adenocarcinomacomparedtotheoppositestate. Thirtyonepatientsf41%)failedtocomplete3or morecyclesofinitialchemotherapymainlydueto intolerabletoxicitiesorsubiectiverefuse.Atthe dateofAprill,2009.20patients(27%)werestill continuinggefitinibtreatmentand43patients(57%, hadrecordeddeath.Thereasonsofdeathwerelung cancer.relatedwiththeexceptionofacute myocardialinfarctionforonly1patient.The medianintervaloffo1low.upwas23.0mr6.545.7

    m1.

    Tolerability

    Integratedsafetydatawerecollectedduringthe gefitinibphaseinallpatientssummarizedinTable 2.Themostcommontoxicitieswereskinrashand diarrhea,andmostofthepatientsjustexperienced Grade1/2toxicitieswhichrelivedgraduallyinthe treatmentperiodacrossthetwogroups.Grade3/4 skinrashordiarrheawasobservedin4patients (6%)andonly1patient(2%)developedgrade3 hepaticdamage,whorestartedgefitinibtreatment afterrecoverybecauseofheapprotectedmedicine.

    Nopatientsexperiencedpneumonitis,fibrosis, hematologictoxicitiesoranyothergrade3and4 nonhematologictoxicitiessuchasfatigueand nausea/vomitinginthepresentpopulation.There

wasnogefitinib-relateddeath.

    Efficacy

    Clinicalinformationwasnotavailableforall patients.Tumorresponsewasavailablefor73of75 patients(bothnodata).Theoverallresponserate was37%(27of73):1CRand26PRs.Twenty.nine percent(2l0f731hadSD.Thediseasecontrolrate fCR+PR+SD)was66%.Survivaldatawere

    availableforentireenrolledpatients.MedianPFS was17.13monthsr95%confidenceinterval (95%CI),14.74-19.531.MedianOSwas26.13 ChinJCancerRes21{3):I.9.2009www.

    springerlink.com

    months(95%CI,22.7729.49).1and2year

    survivalrateswere89.3%and34.7%.respectively (Figure1Aand1B).

    C0rrelati0nsofClinicalCharacteristics/EGFR MutationStatuswithSurvival

    Histologicalsampleswereavailablefrom62 patientsforEGFRmutationdetectionwhich

    showedEGFRmutationsin27patients(44%)and wildtypein35patients(56%).EGFRmutationrate seemedtobehighinfemales,neversmokersand

    patientswithadenocarcinomaorrash,butthere wasnosignificantstatisticaldifference(Table31. KaplanMeiermethodindicatedsignificantly longermedianPFSonlyinpatientsharboring EGFRmutations(P=0.019).Moreover.patients whoobtainedtumorresponse(CR+PR)orcarried EGFRmutationorunderwentrashtendedto

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